Homozygous PiZZ Alpha1PI deficiency is associated with reduction in serum concentrations of Alpha1PI and with the development of pulmonary emphysema. Nevertheless, a number of PiZZ individuals do not develop clinical lung involvement. There is also wide variability in the extent of destructive lung disease in the affected Alpha1PI-deficient population even when the absolute serum level of Alpha1PI and cigarette smoking are taken into consideration. We have recently identified expression of Alpha1PI in human mononuclear phagocytes, including alveolar macrophages, raising the possibility that local alveolar expression of Alpha1PI is a determinant in development of lung disease. We will examine cellular and extracellular variables that determine net Alpha1PI expression in normal (PiMM) and deficient (PiZZ, PiSZ) individuals. Since the integrity of the lung is thought to be maintained by a balance of elastase and anti-elastase in a microenvironment that is constantly confronted by elastase, these enzymes must be considered among the variables that affect net local Alpha1PI expression. In preliminary experiments, we have demonstrated a substantial dose-dependent increase in Alpha1PI expression in blood monocytes and alveolar macrophages incubated in medium containing serine elastase. The effects of elastase on Alpha1PI expression in mononuclear phagocytes will be the major focus of this project, but this effect will also be examined in the context of other potential variables including cellular maturation, tissue specificity, other products of mononuclear phagocytes, products elaborated by other cells locally (lymphokines) and remotely (sex steroid hormones, adrenal corticosteroids) and constituents of the extracellular matrix.